Urinary Excretion Of Vasopressin Research Articles

Increased urinary antidiuretic hormone excretion by imipramine.

Seven normal healthy individuals and ten depressive patients treated with imipramine (75 mg orally) were evaluated for their urinary ADH profile. It was observed that imipramine treated patients excreted higher amounts of urinary ADH (10.6 +/- 0.83 mU/hr) as compared to the control subjects (2.6 +/- 0.35 mU/hr) (P less than 0.01). Blood pressure in both groups was within the normal range.

Steroid hormone release as well as renal water and electrolyte excretion of mice expressing PKB/SGK-resistant GSK3

Insulin and insulin-like growth factor (IGF1) participate in the regulation of renal electrolyte excretion. Insulin- and IGF1-dependent signaling includes phosphatidylinositide-3 (PI3)-kinase, phosphoinositide-dependent kinase PDK1 as well as protein kinase B (PKB) and serum and glucocorticoid inducible kinase (SGK) isoforms, which in turn phosphorylate and thus inhibit glycogen synthase kinase GSK3alpha,beta. Replacement of the serines in the PKB/SGK consensus sequences by alanine (gsk3 ( KI )) confers resistance of GSK3 to PKB/SGK. To explore the role of PKB/SGK-dependent inhibition of GSK3 in the regulation of water/electrolyte metabolism, mice carrying the PKB/SGK resistant mutant (gsk3 ( KI )) were compared to their wild-type littermates (gsk3 ( WT ) ). Body weight was similar in gsk3 ( KI ) and gsk3 ( WT ) mice. Plasma aldosterone at 10 A.M: . and corticosterone concentrations at 5 P.M: . were significantly lower, but 24-h urinary aldosterone was significantly higher, and corticosterone excretion tended to be higher in gsk3 ( KI ) than in gsk3 ( WT ) mice. Food and water intake, fecal excretion, glomerular filtration rate, urinary flow rate, urine osmolarity, as well as urinary Na+, K+, urea excretion were significantly larger, and plasma Na+, urea, but not K+ concentration, were significantly lower in gsk3 ( KI ) than in gsk3 ( WT ) mice. Body temperature was significantly higher in gsk3 ( KI ) than in gsk3 ( WT ) mice. When allowed to choose between tap water and saline, gsk3 ( WT ) mice drank more saline, whereas gsk3 ( KI ) mice drank similar large volumes of tap water and saline. During high-salt diet, urinary vasopressin excretion increased to significantly higher levels in gsk3 ( KI ) than in gsk3 ( WT ) mice. After water deprivation, body weight decreased faster in gsk3 ( KI ) than in gsk3 ( WT ) mice. Blood pressure, however, was significantly higher in gsk3 ( KI ) than in gsk3 ( WT ) mice. The observations disclose a role of PKB/SGK-dependent GSK3 activity in the regulation of steroid hormone release, renal water and electrolyte excretion and blood pressure control.

Disturbed water balance in Ku86−/‐ mice

High NaCl induces DNA breaks in cells in culture and in the kidney inner medulla in vivo. Ku86 binds to broken ends of damaged DNA and facilitates DNA repair. Ku86 deficiency compromises adaptation of cells to high NaCl, resulting in cellular hypertrophy, cell cycle arrest and chromosomal breakage (PNAS 102:10730,2005). We hypothesized that the renal function of Ku86−/‐ mice might be impaired because of increased sensitivity of their renal medullary cells to the high NaCl to which they are normally exposed as part of the urinary concentrating mechanism. To analyze the ability of Ku86−/‐ mice to maintain water balance, mice were subjected to different regimes of water consumption. During free access to water, Ku86−/‐ mice drink much more water leading to greater urine volume (2.45*±0.26 vs 1.11±0.09 ml/20g of body weight (BW)), and decreased urine osmolality compared to wild type mice. However, their urinary vasopressin excretion (U‐AVP) is significantly higher (271±76* vs 136±22 pg/24h per 20 g of BW). U‐AVP dramatically increases in Ku86−/‐ mice when water is limited to 3ml per 5g of gel food (599±74* vs 175±30 pg/24h) and they lose weight. Water restriction to 1.7ml/5g causes further weight loss in Ku86−/‐ mice. We conclude that Ku86−/‐ mice do not adapt normally to water restriction, possibly due to decreased responsiveness of renal collecting ducts to vasopressin. Supported by the Intramural Programs of NHLBI and NCI.

Effects of Gum Arabic ( Acacia senegal) on Water and Electrolyte Balance in Healthy Mice

Gum arabic (GA) is a dietary fiber derived from the dried exudates of Acacia senegal. It is widely used in both the pharmaceutical and food industries as an emulsifier and stabilizer. It is also used in the traditional treatment of patients with chronic kidney disease in Middle Eastern countries. However, the effects of GA on renal function remain ill-defined. We explored the effects of GA on the water and electrolyte balance of healthy wild-type 129S1/SvImJ mice (n = 18). Feces and urine were collected in metabolic cages before and after 3 or 14 days of treatment with 10% GA in drinking water. The GA solutions contained particularly high concentrations of Ca2+, Mg2+, and K+. Because of enhanced uptake, treatment with GA significantly increased both the intestinal and renal excretion of Mg2+ and Ca(2+). The latter was accompanied by decreased urinary excretion of inorganic phosphate and decreased plasma concentrations of 1,25-dihydroxy vitamin D. Moreover, GA significantly increased fecal weight and Na+ excretion. Gum arabic increased 24-h creatinine clearance (from 283 +/- 35 to 382 +/- 40 muL/min [SEM]) and urinary antidiuretic hormone excretion, and decreased daily urine output (from 1.8 +/- 0.2 to 1.2 +/- 0.1 mL/24 h) as well as the urinary excretion of Na(+) (from 226 +/- 22 to 196 +/- 19 mumol/24 h). In conclusion, treatment with GA resulted in moderate but significant increases of creatinine clearance and altered electrolyte excretion, i.e., effects favorable in renal insufficiency.

Vasopressin regulation of inner medullary collecting ducts and compensatory changes in mice lacking adenosine A1 receptors

Activation of adenosine A(1) receptors (A(1)R) can inhibit arginine vasopressin (AVP)-induced cAMP formation in isolated cortical and medullary collecting ducts. To assess the in vivo consequences of the absence of A(1)R, we performed experiments in mice lacking A(1)R (A(1)R(-/-)). We assessed the effects of the vasopressin V(2) receptor (V(2)R) agonist 1-desamino-8-d-arginine vasopressin (dDAVP) on cAMP formation in isolated inner medullary collecting ducts (IMCD) and on water excretion in conscious water-loaded mice. dDAVP-induced cAMP formation in isolated IMCD was significantly greater ( approximately 2-fold) in A(1)R(-/-) compared with wild-type mice (WT) and, in contrast to WT, was not inhibited by the A(1)R agonist N6-cyclohexyladenosine. A(1)R(-/-) and WT had similar basal urinary excretion of vasopressin, expression of aquaporin-2 protein in renal cortex and medulla, and acute increases in urinary flow rate and electrolyte-free water clearance in response to the V(2)R antagonist SR121463 or acute water loading; the latter increased inner medullary A(1)R expression in WT. Dose dependence of dDAVP-induced antidiuresis after acute water loading was not different between the genotypes. However, A(1)R(-/-) had greater inner medullary expression of cyclooxygenase-1 under basal conditions and of the P2Y(2) and EP(3) receptor in response to water loading compared with WT mice. Thus vasopressin-induced cAMP formation is enhanced in isolated IMCD of mice lacking A(1)R, but the adenosine-A(1)R/V(2)R interaction demonstrated in vitro is likely compensated in vivo by multiple mechanisms, a number of which can be "uncovered" by water loading.

Effects of Prenatal Ethanol and Choline on Urinary Vasopressin Excretion in the Rat

Prenatal ethanol (PE) exposure in rats increases water turnover and reduces arginine vasopressin (AVP) synthesis, storage, and release. Supplemental choline (SC) fed to pregnant rats while consuming alcohol normalizes water balance and AVP of offspring. Markers of fetal alcohol exposure are needed for people with mild symptoms. Lowered urinary AVP excretion (U[AVP]V) could provide a noninvasive diagnostic marker and SC should normalize the reduced U[AVP]V. Pregnant rats were fed one of four liquid diets; a control or an ethanol diet (35% of calories from ethanol) from day (D)7–21 of pregnancy with half of the rats fed SC (223 mg/100 ml liquid diet) from D10–21. At 8 weeks of age the offspring were placed in metabolic cages for 4 days. U[AVP]V was measured on D4. Increased water turnover in PE exposed rats was not accompanied by reduced U[AVP]V, but SC nearly doubled the U[AVP]V regardless of the PE exposure, and normalized water turnover. While these results in rats do not support the use of U[AVP]V as marker for PE exposure, they suggest an AVP mediated mechanism of SC correction of the polydipsia and polyuria. Supported in part by a Research Centers in Minority Institutions award, P20 RR11091.

Effects of Ibuprofen and Indomethacin on Urinary Antidiuretic Hormone Excretion in Preterm Infants Treated for Patent Ductus Arteriosus

Objective: To compare the effects of intravenous ibuprofen and indomethacin for treatment of patent ductus arteriosus (PDA) on urinary antidiuretic hormone (ADH) excretion, as a cause of oliguria. Study Design: Forty-four respiratory distress syndrome prematures (≤34 weeks’ gestation) with PDA received either ibuprofen (n = 22) in an initial dose of 10 mg/kg followed by two doses of 5 mg/kg each after 24 and 48 h or three doses at 12-hour intervals of indomethacin (n = 24), 0.2 mg/kg, both infused continuously over a period of 15 min. Urinary ADH excretion, diuresis, serum creatinine, urinary sodium, fractional excretion of sodium, and urinary osmolality were measured before and after treatment. Results: Indomethacin treatment caused a significant decrease in urinary ADH excretion (21.8 ± 20.8 vs. 13.8 ± 12.9 pg/ml; p < 0.05), along with a significant reduction in urinary sodium (92.1 ± 36.1 vs. 64.8 ± 35.6; p < 0.05), fractional excretion of sodium (68.5 ± 37.1 vs. 45.6 ± 37.1; p < 0.05), and urinary osmolality (276.2 ± 103.9 vs. 226.4 ± 60.3; p < 0.05). Ibuprofen treatment did not modify urinary ADH excretion and caused a statistically insignificant decrease in urinary sodium and in fractional excretion of sodium. Conclusions: Compared with ibuprofen, indomethacin caused a significant reduction in urinary ADH excretion and a significant decrease in urinary sodium and osmolality.

Vasopressin, cortisol, and catecholamine concentrations in dogs with dilated cardiomyopathy

To evaluate plasma concentrations and urinary excretion of vasopressin and cortisol and urinary excretion of catecholamines in dogs with dilated cardiomyopathy (DCM). 15 dogs with clinical signs of DCM, 15 dogs with preclinical DCM, and 15 control dogs. Physical examinations, thoracic radiography, ECG, and echocardiography were performed on all dogs. Blood and urine samples were collected. Plasma concentration of vasopressin and the urine cortisol-to-urine creatinine ratio were significantly increased in dogs with clinical signs of DCM and dogs with preclinical DCM, compared with control dogs. Plasma vasopressin concentration was significantly higher in dogs with clinical signs of DCM, compared with dogs with preclinical DCM. Urine vasopressin-to-urine creatinine ratio was significantly increased in dogs with clinical signs of DCM, compared with dogs with preclinical DCM and control dogs. Urine epinephrine-to-urine creatinine ratio and urine norepinephrine-to-urine creatinine ratio were significantly increased in dogs with clinical signs of DCM, compared with control dogs. Plasma concentration of cortisol and urine dopamine-to-urine creatinine ratio did not differ significantly among groups. According to this study, the neuroendocrine pattern is changed in dogs with preclinical DCM. These changes are even more pronounced in dogs with clinical signs of DCM. Analysis of concentrations of vasopressin, cortisol, and catecholamines may aid in identification of the clinical stages of DCM. These findings may also provide a basis for additional studies of the possible beneficial effects of vasopressin antagonists and beta-adrenergic receptor antagonists in the treatment of dogs with congestive heart failure and DCM.

Chronic reductions in carotid blood flow cause salt-sensitive hypertension in rats

We determined whether chronic reductions in carotid blood flow elicit salt-sensitive hypertension through regulation of the brain renin-angiotensin system (RAS). Both internal carotid arteries of male Wistar rats were ligated over a 1-week period. Carotid-ligated or sham-operated rats were treated with a high-salt (8% NaCl diet and 1% NaCl drinking water) or low-salt (0.3% NaCl diet and distilled water) diet for 6 weeks. At the end of the experiment, expression of the RAS mRNAs in the brain was measured. Effects of a 6-day intracerebroventricular infusion of CV-11974, a selective non-peptide angiotensin II type 1 (AT1) receptor blocker, were investigated in carotid-ligated rats administered high-salt diet. High-salt administration increased systolic arterial pressure compared with low-salt administration in sham-operated rats [168 +/- 4 mmHg (n = 10) versus 149 +/- 3 mmHg (n = 10), P < 0.001] and in carotid-ligated rats [202 +/- 5 mmHg (n = 10) versus 153 +/- 2 mmHg (n = 10), P < 0.0001]. Systolic arterial pressure, urinary excretion of vasopressin and norepinephrine, and expression of renin, angiotensin I converting enzyme, and AT1 receptor mRNAs in the hypothalamus were greater in carotid-ligated rats than in sham-operated rats treated with high salt. In contrast, these parameters did not differ between carotid-ligated and sham-operated rats treated with low salt. Intracerebroventricular infusion of CV-11974 abolished the increase in these parameters in carotid-ligated rats treated with the high-salt diet. Chronic reductions in carotid blood flow may cause salt-sensitive hypertension in normotensive rats by activating the hypothalamic RAS.

THE CIRCADIAN RHYTHM OF URINE PRODUCTION, AND URINARY VASOPRESSIN AND PROSTAGLANDIN E2 EXCRETION IN HEALTHY CHILDREN

In adults and adolescents the transition from day to night is followed by a pronounced decrease in diuresis, as well as reduction in the amount of osmotically active substances excreted. We investigate the circadian variations in urine production in healthy children 3 to 14 years old. A total of 92 children completed urine collections in 2 consecutive days to be analyzed for electrolytes, urea, creatinine, osmolality, vasopressin and prostaglandin E2. We found a marked reduction in urine output during the night (43.41 +/- 18.53 to 25.69 +/- 12.71 ml per hour) accompanied by a decrease in the amount of electrolytes excreted (sodium 4.44 +/- 2.09 to 2.66 +/- 1.55 mmol per hour and potassium 2.38 +/-0.96 to 0.90 +/- 0.54 mmol per hour). Age and gender did not influence the observed circadian rhythm in the quantity and quality of urine production. Urinary excretion of vasopressin did not seem to reflect the circadian variations previously described for the plasma levels of the hormone. Prostaglandin E2 showed a clear circadian variation with a 30% decrease at night (32.2 +/- 19.0 to 22.0 +/- 12.6 ng/mmol creatinine). Healthy children exhibit pronounced circadian variations in the amount and composition of urine output with a decrease in nocturnal diuresis and excretion of osmotically active solutes. In the age range of 3 to 14 years neither age nor gender seems to affect this rhythm. Vasopressin-to-prostaglandin E2 excretion ratio appears to be of importance for regulation of urine production.

Symposium

Symposium

Impaired Urinary Concentrating Ability in Genetically Polyuric Mice

Newly recognized strain of mice with hereditary polyuria (PUS mice) was characterized. Polyuria was inherited as a single autosomal-recessive trait. At 15 weeks, PUS mice excreted hypotonic (urine osmolality: PUS;270.8 ± 15.5 vs. cont.; 3,228.6 ± 163.6 mosm/kg) polyuria (urine volume: PUS; 25.0 ± 1.5 vs. cont.; 1.1 ± 0.1 ml/day). In PUS mice, plasma osmolality was slightly elevated as well as urinary excretion of vasopressin (AVP). Although PUS mice could concentrate urine after 24 h water deprivation, urine osmolality remained low. Blunted response to continuous infusion of dDAVP, a synthetic V2 agonist, was also observed. These in vivo studies indicated renal resistance to AVP contributed to the polyuria in this strain of mice. Microanalysis of isolated tubular segments revealed that AVP-induced cAMP accumulation in cortical collecting ducts (CCD) of PUS mice was significantly lower (60%) with or without a phosphodiesterase inhibitor, IBMX. Vasopressin induced similar cAMP accumulation in medullary ascending limbs of Henle (MAL), and medullary collecting ducts (MCD) between PUS and control mice. In CCDs, PUS mice had low basal adenylate cyclase (AdC) activity and responded less to AVP and forskolin stimulation than control mice. No difference in cyclic AMP phosphodiesterase activity was detected between control and PUS mice. These results indicate that impaired cAMP accumulation due to low AdC activity may be related to the impaired renal concentrating ability observed in this new strain of mice.

Decreased nocturnal urinary antidiuretic hormone excretion in enuresis is increased by imipramine.

To assess the role of integrated nocturnal antidiuretic hormone (ADH) secretion in children with enuresis, and possible modifications induced by treatment with imipramine. The morning plasma ADH and nocturnal urinary ADH integrated concentrations were measured in 18 consecutive enuretic children (patients) and 21 age- and sex-matched controls admitted for minor treatment. Diurnal and nocturnal urine production, and plasma and urinary osmolality were also determined; lumbosacral radiography and uroflowmetry were undertaken in the patients. The assessments were repeated after 14 days of treatment with imipramine hydrochloride (orally, 20 mg/night). Half the patients had occult spinal malformations but the uroflowmetry results were all within the normal range. The median (95% confidence interval, CI) urinary ADH integrated concentrations were markedly lower in patients, at 29.7 (22.1-37.3) vs 63.0 (35.1-90.8) pg/mL/h (P = 0.03) than in controls. Plasma ADH levels were significantly increased by imipramine (0.64 to 1.47 pg/mL, 95% CI, 0.40-0.89 vs -0.26-3.2; P < 0.001), as were nocturnal urinary ADH integrated concentrations, at 29.7 (22.1-37.3) vs 59.0 (37.3-80.6) pg/mL/h (P < 0.001), and morning plasma osmolality decreased, from 298.5 (294.5-302.5) to 294.9 (292.4-297.3) mosmol/kg (P = 0.003), as was the 24-h fluid intake, from 983 (721-1245) to 666 (435-897) mL (P = 0.004). We conclude that enuretic children have a lower nocturnal ADH excretion; imipramine restores nocturnal ADH excretion, increases morning plasma ADH levels, and causes consistent changes in other biochemical variables.

Vasopressin does not effect hypertension caused by long-term nitric oxide inhibition.

Nitric oxide attenuates both vasopressin-induced vasoconstriction and vasopressin release. We tested whether hypertension and renal dysfunction elicited by chronic inhibition of nitric oxide (NO) synthesis using N(G)-nitro-L-arginine (L-NNA) could be mediated in part by vasopressin V(1A) receptors. Male rats were treated orally for 6 weeks with L-NNA (15 mg/kg per day), a nonpeptide V(1A) receptor antagonist (2S)-1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3, 4-dimethoxybenzene-sulfonyl)-3-hydroxy-2, 3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide (SR 49059, 30 mg/kg per day), or a combination of SR 49059 and L-NNA (same doses), or they received no treatment. Both drugs were added to the food. Measurements were performed in conscious rats (urine collection in metabolic cages, tail-cuff arterial pressure) and at the end of the study in anesthetized rats (clearance measurements). L-NNA produced sustained hypertension, decreased glomerular filtration rate, and increased renal vascular resistance, plasma renin activity, and urinary albumin excretion. SR 49059 had no effect per se on these parameters and also did not attenuate the hypertension and renal dysfunction induced by L-NNA. Surprisingly, SR 49059 potentiated L-NNA-induced hypertension at the end of the 6-week treatment. However, the blood pressure response and the renal and mesenteric vasoconstriction elicited by exogenous vasopressin were attenuated in rats treated with SR 49059. L-NNA did not change plasma vasopressin concentration or 24-hour urinary vasopressin excretion. Our findings suggest that activation of vasopressin V(1A) receptors does not contribute to the hypertension and renal dysfunction induced by chronic NO synthesis inhibition. They also document unchanged plasma vasopressin concentration in NO-deficient hypertension.

Role of FMRFamide-activated brain sodium channel in salt-sensitive hypertension.

FMRFamide, a cardioexcitatory neuropeptide, directly activates a newly cloned amiloride-sensitive sodium channel that is expressed specifically in the brain and blocked by benzamil hydrochloride. In the present study, we investigated the effects of short- and long-term intracerebroventricular infusion of FMRFamide on arterial pressure, sympathetic activity, vasopressin release, and brain renin-angiotensin system genes in rats and studied the role of FMRFamide-activated brain sodium channels in salt-sensitive hypertension. The intracerebroventricular preinjection of FMRFamide and subsequent intracerebroventricular infusion of 0.15 mol/L NaCl increased mean arterial pressure (FMRFamide: 30 nmol/kg +13+/-2.6 mm Hg, P<0.01; 100 nmol/kg +21+/-1.8 mm Hg, P<0.01), heart rate, abdominal sympathetic activity, and plasma vasopressin concentration compared with vehicle. The intracerebroventricular copreinjection with either benzamil or CV-11974 abolished these increases. In rats administered a high-salt diet (8% NaCl), the continuous intracerebroventricular infusion of FMRFamide (50 and 200 nmol. kg(-1). d(-1)) for 5 days increased mean arterial pressure, heart rate, urinary excretion of vasopressin and norepinephrine, and mRNAs of renin, angiotensin I-converting enzyme, and angiotensin II type 1 receptor in hypothalamus and brain stem compared with vehicle. These increases were abolished by intracerebroventricular coinfusion of benzamil. In rats administered a low-salt diet (0.3% NaCl), however, increases in these variables were smaller than those in rats receiving a high-salt diet. Together, these findings suggest that brain FMRFamide-activated sodium channels may be involved in the mechanism of salt-sensitive hypertension through regulation of the brain renin-angiotensin system.

Endocrinological abnormalities in angiotensinogen-gene knockout mice: studies of hormonal responses to dietary salt loading.

Physiological roles of the renin-angiotensin system in maintaining blood pressure and sodium-water balance in angiotensinogen gene-knockout mice were evaluated with special reference to endogenous pressor substances. Angiotensinogen-gene knockout mice and control mice were fed a 0.3 or 4% NaCl diet for 2 weeks. Systolic blood pressure and urinary excretions of electrolytes, creatinine, aldosterone, adrenaline, noradrenaline, dopamine and vasopressin were measured. About 60% of our angiotensinogen-gene knockout mice did not survive until weaning. These mice presented with hypotension and polyuria. Urinary excretion of aldosterone from such mice was significantly lower (not detected) than that from control mice (2.0+/-0.3 pg/mg creatinine). In contrast, urinary excretion of vasopressin from angiotensinogen-gene knockout mice (0.7+/-0.1 ng/mg creatinine) was greater than that from control mice (0.3+/-0.1 ng/mg creatinine), and those of adrenaline and of noradrenaline were similar for knockout and control mice. After salt loading (a 4% NaCl diet), angiotensinogen-gene knockout mice exhibited a significant increase in systolic blood pressure (from 68.3+/-2.9 to 95.9+/-5.9 mmHg), significant decreases in urinary excretions of adrenaline (from 65+/-8 to 40+/-7 pg/mg creatinine) and noradrenaline (from 467+/-48 to 281+/-41 pg/mg creatinine) and no change in excretion of vasopressin compared with such mice fed a 0.3% NaCl diet The present results with angiotensinogen-gene knockout mice confirm that the renin-angiotensin system plays fundamental roles in maintaining the blood pressure and sodium-water balance. Because the vasopressin and catecholaminergic systems may be altered by lack of angiotensin in angiotensinogen-gene knockout mice, these systems perhaps are not able to restore blood pressure and sodium-water depletion to normal levels in these mice.

Benzamil blockade of brain Na+ channels averts Na(+)-induced hypertension in rats.

To determine the possible involvement of brain amiloride-sensitive Na+ channels in Na(+)-induced hypertension, we investigated the effects of benzamil hydrochloride, a specific blocker of these Na+ channels, on the acute pressor mechanisms of intracerebroventricular infusion of hypertonic NaCl and the continuous pressor mechanisms of Na(+)-induced chronic hypertension, such as deoxycorticosterone acetate-salt hypertensive or stroke-prone spontaneous hypertensive rats, and of non-Na(+)-induced hypertension, such as renovascular hypertensive rats. Intracerebroventricular preinjection with benzamil (1 or 10 nmol/kg) abolished the increase in mean arterial pressure, heart rate, abdominal sympathetic discharge, and plasma vasopressin concentration induced by an acute increase in cerebrospinal Na+ concentrations at intracerebroventricular infusion of 1.5 M hypertonic NaCl. Continuous intracerebroventricular infusion of benzamil (1 or 10 nmol.kg-1.day-1) for 7 days attenuated Na(+)-induced chronic hypertension in both deoxycorticosterone acetate-salt and stroke-prone spontaneous hypertensive rats, accompanied by reduction of urinary excretion of vasopressin and norepinephrine but not in renovascular hypertensive rats. Intravenous infusion of benzamil (10 nmol.kg-1.day-1) for 7 days affected neither arterial pressure nor urinary excretion of vasopressin and norepinephrine in either model of hypertension. Benzamil-blockable brain amiloride-sensitive Na+ channels are expected to function as one of the Na+ receptors in the brain and to be involved in the pressor mechanism of Na(+)-induced hypertension.

Genetic deficiency of angiotensinogen produces an impaired urine concentrating ability in mice

Angiotensinogen gene-knockout (Atg-/-) mice lacking angiotensin II exhibit chronic hypotension. The present study was designed to investigate pathophysiology of Atg-/- mice from the renal functional view. Wild-type (Atg+/+) and Atg-/- mice at 10 weeks of age were housed in metabolic cages for 24-hour urine collection. When provided free access to water, Atg-/- mice showed an increased urine output and a decreased urine osmolality compared with Atg+/+ mice. Urinary excretion and plasma levels of vasopressin were significantly higher in mutant mice than in wild-type mice. On the other hand, urinary excretion of aldosterone in mutant mice was suppressed to the levels under the detection limit of the assay system. The mean plasma aldosterone level of Atg-/- mice was suppressed to 30% of that of Atg+/+ mice. Plasma levels of creatinine, endogenous creatinine clearance, and urinary electrolyte excretion were not different between these mice. In Atg+/+ mice, urine osmolality was markedly increased from 1929 +/- 21 to 3314 +/- 402 mOsm/kg during water deprivation, whereas this parameter in Atg-/- mice did not change significantly (from 1413 +/- 121 to 1590 +/- 92 mOsm/kg). Urinary vasopressin excretion increased during water deprivation from 0.24 +/- 0.04 and 0.70 +/- 0.08 to 0.42 +/- 0.06 and 2.31 +/- 0.35 ng/mg creatinine in wild-type and mutant mice, respectively. Histologic study revealed interstitial inflammation, and atrophic changes in the tubules and papilla in Atg-/- mice. In conclusion, a genetic deficiency of angiotensinogen produced an impaired urine concentrating ability and tubulointerstitial lesions, indicating the critical role of angiotensinogen in developing normal tubular function and construction.

DEVELOPMENT OF POLYURIA IN TSUKUBA HYPERTENSIVE MICE CARRYING HUMAN RENIN AND ANGIOTENSINOGEN GENES

1. Tsukuba hypertensive mice (THM) carry both human renin and angiotensinogen genes, and develop hypertension. The animal has high levels of renin activity and angiotensin II concentration in the plasma. 2. Urinary excretion in THM was greater than in the control animal, non-transgenic C57BL/6j. THM showed a greater amount of daily water intake. The osmolality of 24 h urine was lower than that of the control animal. 3. When water was deprived for 12 h and then loaded with 0.25 mL/10 g bodyweight, the osmolality of urine at the first 0-3 h period was the same in THM and control, but significantly lower in THM at the following 3-6 h period, indicating that the urine concentrating activity is insufficient in THM compared with the control animal. 4. Urinary excretion of vasopressin was significantly higher in THM. Plasma aldosterone concentration and urinary excretion of aldosterone were also higher in THM. Plasma potassium level was significantly low. 5. The mechanism underlying the pathophysiology of polyuria is not totally explained; however, hypokalaemia, which was probably the result of hyperaldosteronism, may be at least partially involved, since hypokalaemia is considered to be a factor hampering the action of vasopressin for concentration of urine at the site of the collecting duct of the kidney.

The effect of cholinoceptor agonists and neurotoxins on the release of vasopressin in the rat in relation to the subunit composition of the cholinoceptor

The effects of cholinoceptor agonists and neurotoxins on the release of vasopressin and oxytocin have been investigated in water-loaded rats under ethanol anaesthesia. Release of vasopressin was monitored by antidiuretic responses accompanied by increased urinary excretion of vasopressin. The rate of excretion of oxytocin-like radioimmunoreactivity was measured as an indicator of oxytocin release. Both nicotine and cytisine caused a preferential release of vasopressin. The release by nicotine was not inhibited by α- or neuronal-bungarotoxin. Neosurugatoxin blocked the release by cytisine. Comparison with the effects of these agents on combinations of α and β subunits expressed in oocytes suggests that the central cholinoceptors mediating release of vasopressin are similar to those at autonomic ganglia and may contain a β4 subunit.